GC-MS Profiling of Ethanol-Extracted Polyherbal Compounds from Medicinal Plant (Citrullus colocynthis, Curcuma longa, and Myristica fragrans): In Silico and Analytical Insights into Diabetic Neuropathy Therapy via Targeting the Aldose Reductase.

Diabetic neuropathy is one of the severe complications of diabetes, which affects the quality of life in a patient and increases the risk of amputations and chronic wounds. Current therapeutic approaches are symptomatically oriented, focusing on comfort and non-inflammatory aspects without addressing the mechanism or molecular target of the disease. The present study investigates the therapeutic effects of an ethanolic polyherbal extract from Citrullus colocynthis (Bitter Apple), Curcuma longa (Turmeric), and Myristica fragrans (Nutmeg) using advanced in silico and analytical methods. According to the findings, PHE showed the presence of a total of 39 bioactive compounds in GC-MS analysis, which include alcohols, fatty acids, terpenoids, esters, neolignans, phenylpropanoids, and steroids. Three of the compounds--4-isopropyl-1,6-dimethyl-1,2,3,4-tetrahydronaphthalene (-11.4 kcal/mol), (1S,2R)-2-(4-allyl-2,6-dimethoxyphenoxy)-1-(3,4,5-trimethoxyphenyl)-1-propanol (-9.8 kcal/mol) and (S)-5-Allyl-2-((1-(3,4-dimethoxyphenyl)propan-2-yl)oxy)-1,3-dimethoxybenzene (-10.3 kcal/mol)-followed the Lipinski rule and showed the binding affinity with aldol reductase. Docking experiments showed that compound 4-isopropyl-1,6-dimethyl-1,2,3,4-tetrahydronaphthalene (-11.4 kcal/mol) has high-affinity binding to aldose reductase, an enzyme involved in diabetic neuropathy pathophysiology, whereas molecular dynamics simulations show long-range persistence of the interaction of (S)-5-Allyl-2-((1-(3,4-dimethoxyphenyl)propan-2-yl)oxy)-1,3-dimethoxybenzene with aldol reductase in physiological conditions. Therefore, this combination of herbal therapy and advanced computational/analytical techniques could be leading towards innovative, multi-targeted therapies against diabetic neuropathy. Nevertheless, further studies in vivo are required to confirm the efficacy, safety, and pharmacokinetics of the PHE in biological systems.